This project describes the isolation of DNA probes linked to the site in the human X chromosome involved in fragility of the chromosome under some growth conditions ("fragile X site") and known to be associated with a high incidence cause of mental retardation. Such sequences may be useful in understanding the molecular defects responsible for chromosomal fragility, in elucidating the pathogenesis of the central nervous system disorder and in providing tools for its detection. We plan to take advantage of the known high degree of synteny of mammalian X chromosomal loci to investigate the possibility that large regions of the human and mouse X chromosomes have similar or identical genetic organization and to determine the fine structure genetic map of the region of the mouse X chromosome homologous to the human fragile site and its flanking regions. We shall use a combination of in situ hybridization, mapping in recombinant inbred (RI) mouse strains and linkage analysis in human pedigrees to test and prove tight linkage of probes to fragile X site, and then apply new methods of chromosome "walking" to isolate sequences that span the site itself.